Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Migration of endothelial cells induced by vascular endothelial growth factor (VEGF) is a critical step in angiogenesis. Stimulation of motility by growth factors such as VEGF requires interaction with the signal transduction pathways activated by the extracellular matrix (ECM). Here we demonstrate that the Rac GTPase is the critical intersection activated by type 1 collagen ECM and VEGF during stimulation of endothelial cell motility. To analyze the role of the Rho family GTPases in VEGF-stimulated endothelial cell chemotaxis and ECM-stimulated haptotaxis, we transduced the respective fusion proteins in human foreskin dermal endothelial cells using a Tat peptide from the human immunodeficiency virus Tat protein. VEGF signaling required Rac activation during chemotaxis, and Rac and Cdc42 were activated during haptotaxis on type I collagen. Similar to VEGF, Rac activation induced an increase in endothelial cell stress fiber and focal adhesion. Surprisingly, Rho activation was not present in collagen-induced haptotaxis or stimulation of chemotaxis by VEGF, although Rho induced stress fibers and focal adhesions similar to Rac activation. The result of constitutive Rho activation was an inhibition of haptotaxis. Thus, Rac is required and sufficient for the activation of endothelial cell haptotaxis and VEGF-stimulated chemotaxis.
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PMID:Rho family GTPases regulate VEGF-stimulated endothelial cell motility. 1152 41

Kaposi's sarcoma is a vascular tumor commonly associated with human immunodeficiency virus (HIV)-1 and human herpesvirus (HHV-8) also known as Kaposi's sarcoma-associated herpesvirus. The principal features of this tumor are abnormal proliferation of vascular structures lined with spindle-shaped endothelial cells. HHV-8 may transform a subpopulation of endothelial cells in vitro via viral and cellular gene expression. We hypothesized that among the cellular genes, vascular endothelial growth factors (VEGFs) and their cognate receptors may be involved in viral-mediated transformation. We have shown that HHV-8-transformed endothelial cells (EC-HHV-8) express higher levels of VEGF, VEGF-C, VEGF-D, and PlGF in addition to VEGF receptors-1, -2, and -3. Furthermore, antibodies to VEGF receptor-2 inhibited cell proliferation and viability. Similarly, inhibition of VEGF gene expression with antisense oligonucleotides inhibited EC-HHV-8 cell proliferation/viability. The growth and viability of primary endothelial cells and a fibroblast cell line however were unaffected by either the VEGF receptor-2 antibody or the VEGF antisense oligodeoxynucleotides. VEGF and VEGF receptors are thus induced in EC-HHV-8 and participate in the transformation. Inhibitors of VEGF may thus modulate the disease process during development and progression.
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PMID:Human herpesvirus-8-transformed endothelial cells have functionally activated vascular endothelial growth factor/vascular endothelial growth factor receptor. 1178 94

Treatment of patients with human immunodeficiency virus (HIV) protease inhibitors such as ritonavir can result in increases in CD4(+) T-cell counts that are independent of a reduction in HIV-1 viral load. This lack of correlation between the 2 has led to the identification of additional effects of ritonavir that potentially alter HIV disease pathogenesis. Our previous studies indicated that ritonavir directly affects immune cell activation, proliferation, and susceptibility to apoptosis. We show here that ritonavir inhibited the activation and proliferation of primary endothelial cells and decreased the production of tumor necrosis factor alpha (TNF-alpha) interleukin 6 (IL-6), IL-8, and vascular endothelial growth factor, factors that all contribute to tumor neovascularization and to the development of Kaposi sarcoma (KS) lesions. Ritonavir also suppressed the expression of vascular cell adhesion molecule 1, intercellular adhesion molecule 1, and E-selectin, which correlated with a functional decrease in leukocyte adhesion. Transcriptional activation of nuclear factor-kappaB, as induced by the KS-promoting factor TNF-alpha, the HIV-1 Tat protein, or the human herpesvirus 8 protein ORF74, was inhibited by ritonavir. KS-derived cell lines underwent apoptosis in vitro after treatment with ritonavir at concentrations that are obtained in clinical therapy (3-15 microM). In a KS mouse xenotransplantation model, ritonavir inhibited tumor formation and progression by KS-derived cells. Taken together, these data suggest that ritonavir has antineoplastic effects that are independent from its ability to inhibit the HIV protease.
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PMID:Antitumorigenic effects of HIV protease inhibitor ritonavir: inhibition of Kaposi sarcoma. 1198 35

Because one of the attractive characteristics of human immunodeficiency virus type 1 (HIV-1)-based lentiviral vectors is that it can infect even nondividing cells, a lentivirus-mediated gene delivery system is currently being paid a great deal of attention as an innovative tool for gene transfer into target cells. The purpose of the work was to investigate the efficacy of lentiviral transfer of the LacZ gene into human umbilical vein endothelial cells (HUVECs) and human bone marrow mesenchymal stem cells (HMSCs) in vitro. For the present study, a vesicular stomatitis virus G-protein (VSV-G)-pseudotyped lentiviral vector encoding the E. coli LacZ gene tagged with nuclear localization signal (NLS) was generated in 293T cells by means of the three-plasmid system. The resulting lentiviral vector, LtV-NLS/LacZ, was allowed to infect HUVECs and HMSCs. Approximately 70% of HUVECs were positive for LacZ expression and 50% of HMSCs showed LacZ activity. There was no significant difference in transduction efficacy between early and late-passage phases in both cells. LtV-NLS/LacZ-transduced HUVECs showed gene expression of endothelial markers including CD34 and flt-1 and KDR/flk-1 of vascular endothelial growth factor (VEGF) receptors and had angiogenic potential as efficiently as primarily cultured HUVECs in a Matrigel assay. These findings provide evidence that lentiviral vectors are efficient tools for gene transfer and expression in human endothelial cells and stem cells that could be useful for tissue engineering.
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PMID:Lentiviral transfer of the LacZ gene into human endothelial cells and human bone marrow mesenchymal stem cells. 1238 78

Viral infection of the central nervous system elicits a myriad of cellular, vascular, and neuroimmune factors that contribute to acute, subacute, and chronic damage to the brain. In response to cellular damage, the host is capable of producing trophic factors that may protect neuronal, glial, and endothelial cell populations. Both neurotrophic and angiotrophic factors can also operate by modulating the neuroimmune response, which plays a central role in the pathogenesis of the neurodegenerative process. In this regard, crosstalk signaling among host cells, components of the neuroimmune response, and virus could influence cell fate by production of trophic factors that protect or rescue neurons vulnerable to viral damage. In this context, the main objective of this review is to provide an overview of evidence in support of the role of trophic factors in regulating the neuroimmune response in chronic viral infections of the central nervous system. Special emphasis is placed on the interaction of the human immunodeficiency virus (HIV) Tat protein with endothelial, astroglial, microglial, and neuronal cells, resulting in altered expression of vascular endothelial growth factor, fibroblast growth factor, interleukin-8, and regulation of calcium flux via CXCR2, which directly influences neuronal cell fitness.
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PMID:Role of trophic factors on neuroimmunity in neurodegenerative infectious diseases. 1247 55

Endostatin, a proteolytic fragment of collagen XVIII, is an endogenous inhibitor of tumor angiogenesis that also inhibits choroidal neovascularization. In this study, we assessed the effects of increased intraocular expression of endostatin on vascular endothelial growth factor (VEGF)-induced changes in the retina. After subretinal injection of a pair of gutless adenoviral vectors (AGV) designed to provide tamoxifen-inducible expression of endostatin, diffuse endostatin immunoreactivity was induced thoroughout the retina by administration of tamoxifen. Induction of endostatin in double transgenic mice with doxycycline-induced expression of VEGF in the retina resulted in significant suppression of leakage of intravascular [3H]mannitol into the retina. The ability of endostatin to reduce VEGF-induced retinal vascular permeability was confirmed by using [3H]mannitol leakage and two other parameters, fluorescein leakage and retinal thickness, after subretinal injection of a bovine immunodeficiency lentiviral vector coding for endostatin (BIV-vectored endostatin, or BIVendostatin). Subretinal injection of BIVendostatin resulted in more discrete, less intense staining for endostatin in the retina than that seen with the inducible AGV system, which suggested lower levels and allowed visualization of sites where endostatin was concentrated. Endostatin staining outlined retinal blood vessels, which suggested endostatin binding to a component of vessel walls. More prolonged or higher level expression of VEGF in the retina resulted in neovascularization and retinal detachment, both of which were also significantly reduced by BIVendostatin. These data suggest that endostatin may be an endogenous inhibitor of vasopermeability as well as neovascularization. In patients with diabetic retinopathy, endostatin gene transfer may provide a way to decrease the risk of three causes of visual loss: macular edema, neovascularization, and retinal detachment.
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PMID:Intraocular expression of endostatin reduces VEGF-induced retinal vascular permeability, neovascularization, and retinal detachment. 1267 Aug 75

Immunosuppression associated with human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS) markedly increases the risk for development of several cancers. Despite its dramatic decrease in frequency after the introduction of highly active antiretroviral therapy (HAART), Kaposi's sarcoma (KS) remains the most common neoplastic manifestation of AIDS. KS is a multicentric angioproliferative tumor, characterized microscopically by spindle cells. KS cells produce and respond to angiogenic factors such as basic fibroblast growth factor (bFGF) and vascular endothelial growth factor-A (VEGF-A). In addition to cellular growth factors, the trans-activator HIV protein Tat plays a major role in the pathogenesis of AIDS-related KS by augmenting the angiogenic activities of bFGF and VEGF-A, and activating the VEGF receptor-2. Viral products from the recently described Kaposi's sarcoma-associated herpesvirus (KSHV) also exhibit potent angiogenic activities. KSHV is consistently associated with KS and two lymphoproliferative disorders, primary effusion lymphoma (PEL) and the plasma cell variant of multicentric Castleman's disease (MCD). Several viral genes may contribute to the phenotype of PEL and MCD: among them, a viral homologue of interleukin-6 (vIL-6) has attracted much attention due to its potential to stimulate B cell growth and accelerate angiogenesis via VEGF-A induction. In this review, we summarize current knowledge and hypothesis regarding the cellular and viral angiogenic factors involved in the pathogeneses of AIDS-related malignancies, and discuss novel therapeutic strategies based on targeting pro-angiogenic factors.
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PMID:Targeted inhibition of angiogenic factors in AIDS-related disorders. 1276 89

Endothelial cells (ECs) in normal vessels are poorly transducible by retroviral vectors, which require cell division for gene transduction. Among retroviruses, lentiviruses have the unique ability to integrate their genome into the chromatin of nondividing cells. Here we show that multiply attenuated, self-inactivating, lentiviral vectors transduce both proliferating and growth-arrested human umbilical vein ECs (HUVECs), human coronary artery ECs (HCAECs), and human coronary artery smooth muscle cells (HCASMCs), with high efficacy. Lentiviral vectors containing the enhanced green fluorescence protein (EGFP) transgene driven by either the cytomegalovirus or the elongation factor-1alpha promoter, but not the phosphoglycerate kinase promoter, directed high-level EGFP expression in endothelial and smooth muscle cells. The endothelium-specific Tie2 promoter also directed transgene expression in ECs. Re-insertion of cis-acting sequences from pol of human immunodeficiency virus type 1 (HIV-1) into the vectors improved transgene expression. A lentiviral vector containing the vascular endothelial growth factor transgene promoted EC proliferation and sprouting in vitro. In vivo gene transfer was studied by lumenal infusion of vector containing solutions into rat carotid arteries. Lentivirus-mediated EGFP gene transfer was observed in approximately 5% of ECs. Lentiviral vectors containing the LacZ transgene achieved detectable beta-galactosidase activity in rat arteries, albeit at a lower level compared with adenoviral vectors. This difference was mainly due to the lower concentration of lentiviral vector preparations. Lentivirus-mediated gene transfer was associated with minimal neointimal hyperplasia and scant inflammatory cell infiltrates in the media and adventitia. These observations indicate that lentiviral vectors may be useful for genetic modifications of vascular cells in vitro and in vivo.
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PMID:Multiply attenuated, self-inactivating lentiviral vectors efficiently transduce human coronary artery cells in vitro and rat arteries in vivo. 1569 40

Kaposi's sarcoma (KS) is a highly vascular tumour and is the most common neoplasm associated with human immunodeficiency virus (HIV-1) infection. Growth factors, in particular vascular endothelial growth factor (VEGF), have been shown to play an important role in its development. The role of insulin-like growth factors (IGFs) in the pathophysiology of different tumours led us to evaluate the role of IGF system in KS. The IGF-I receptors (IGF-IR) were identified by immunohistochemistry in biopsies taken from patients with different AIDS/HIV-related KS stages and on KSIMM cells (an established KS-derived cell line). Insulin-like growth factor-I is a growth factor for KSIMM cells with a maximum increase of 3H-thymidine incorporation of 130 +/- 27.6% (P < 0.05) similar to that induced by VEGF and with which it is additive (281 +/- 13%) (P < 0.05). Moreover, specific blockade of the receptor (either by alpha IR3 antibody or by picropodophyllin, a recently described selective IGF-IR tyrosine phosphorylation inhibitor) induced KSIMM apoptosis, suggesting that IGF-IR agonists (IGF-I and -II) mediate antiapoptotic signals for these cells. We were able to identify an autocrine loop essential for KSIMM cell survival in which IGF-II is the IGF-IR agonist secreted by the cells. In conclusion, IGF-I pathway inhibition is a promising therapeutical approach for KS tumours.
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PMID:Insulin-like growth factor-I receptor activity is essential for Kaposi's sarcoma growth and survival. 1581 60

Safe, effective approaches for bone regeneration are needed to reverse bone loss caused by trauma, disease, and tumor resection. Unfortunately, the science of bone regeneration is still in its infancy, with all current or emerging therapies having serious limitations. Unlike current regenerative therapies that use single regenerative factors, the natural processes of bone formation and repair require the coordinated expression of many molecules, including growth factors, bone morphogenetic proteins, and specific transcription factors. As will be developed in this article, future advances in bone regeneration will likely incorporate therapies that mimic critical aspects of these natural biological processes, using the tools of gene therapy and tissue engineering. This review will summarize current knowledge related to normal bone development and fracture repair, and will describe how gene therapy, in combination with tissue engineering, may mimic critical aspects of these natural processes. Current gene therapy approaches for bone regeneration will then be summarized, including recent work where combinatorial gene therapy was used to express groups of molecules that synergistically interacted to stimulate bone regeneration. Last, proposed future directions for this field will be discussed, where regulated gene expression systems will be combined with cells seeded in precise three-dimensional configurations on synthetic scaffolds to control both temporal and spatial distribution of regenerative factors. It is the premise of this article that such approaches will eventually allow us to achieve the ultimate goal of bone tissue engineering: to reconstruct entire bones with associated joints, ligaments, or sutures. Abbreviations used: BMP, bone morphogenetic protein; FGF, fibroblast growth factor; AER, apical ectodermal ridge; ZPA, zone of polarizing activity; PZ, progress zone; SHH, sonic hedgehog; OSX, osterix transcription factor; FGFR, fibroblast growth factor receptor; PMN, polymorphonuclear neutrophil; PDGF, platelet-derived growth factor; IGF, insulin-like growth factor; TGF-beta, tumor-derived growth factor beta; CAR, coxsackievirus and adenovirus receptor; MLV, murine leukemia virus; HIV, human immunodeficiency virus; AAV, adeno-associated virus; CAT, computer-aided tomography; CMV, cytomegalovirus; GAM, gene-activated matrix; MSC, marrow stromal cell; MDSC, muscle-derived stem cell; VEGF, vascular endothelial growth factor.
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PMID:Biological approaches to bone regeneration by gene therapy. 1630 38


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